Journal ArticleDOI
Lymphangiogenic growth factors, receptors and therapies.
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TLDR
Recent results show that the homeodomain transcription factor Prox-1 is an important lymphatic endothelial cell (LEC) fate-determining factor which can induce LEC-specific gene transcription even in blood vascular endothelial cells (BECs), which suggests that the distinct phenotypes of cells in the adult vascular endothelium are plastic and sensitive to transcriptional reprogramming, which might be useful for future therapeutic applications involving endothelial Cells.Abstract:
The lymphatic vasculature is essential for the maintenance of normal fluid balance and for the immune responses, but it is also involved in a variety of diseases. Hypoplasia or dysfuction of the lymphatic vessels can lead to lymphedema, whereas hyperplasia or abnormal growth of these vessels are associated with lymphangiomas and lymphangiosarcomas. Lymphatic vessels are also involved in lymph node and systemic metastasis of cancer cells. Recent novel findings on the molecular mechanisms involved in lymphatic vessel development and regulation allow the modulation of the lymphangiogenic process and specific targeting of the lymphatic endothelium. Recent results show that the homeodomain transcription factor Prox-1 is an important lymphatic endothelial cell (LEC) fate-determining factor which can induce LEC-specific gene transcription even in blood vascular endothelial cells (BECs). This suggests that the distinct phenotypes of cells in the adult vascular endothelium are plastic and sensitive to transcriptional reprogramming, which might be useful for future therapeutic applications involving endothelial cells Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are peptide growth factors capable of inducing the growth of new lymphatic vessels in vivo in a process called lymphangiogenesis. They belong to the larger family which also includes VEGF, placenta growth factor (PlGF) and VEGF-B. VEGF-C and VEGF-D are ligands for the endothelial cell specific tyrosine kinase receptors VEGFR-2 and VEGFR-3. In adult human as well as mouse tissues VEGFR-3 is expressed predominantly in lymphatic endothelial cells which line the inner surface of lymphatic vessels. While VEGFR-2 is thought to be the main mediator of angiogenesis, VEGFR-3 signaling is crucial for the development of the lymphatic vessels. Heterozygous inactivation of the VEGFR-3 tyrosine kinase leads to primary lymphedema due to defective lymphatic drainage in the limbs. Other factors that seem to be involved in lymphangiogenesis include the Tie/angiopoietin system, neuropilin-2 and integrin α9. VEGF-C induces lymphatic vessel growth, but high levels of VEGF-C also resulted in blood vessel leakiness and growth. The VEGFR-3-specific mutant form of VEGF-C called VEGF-C156S lacks blood vascular side effects but is sufficient for therapeutic lymphangiogenesis in a mouse model of lymphedema. As VEGF-C156S is a specific lymphatic endothelial growth factor in the skin, it provides an attractive molecule for pro-lymphangiogenic therapy. This publication was partially financed by Serono. Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology, which took place in Geneva, Switzerland from February 6-9, 2003.read more
Citations
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Journal ArticleDOI
The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions.
TL;DR: Progress in the molecular and biological understanding of the VEGF/VEGFR system provides us with novel and promising therapeutic strategies and target proteins for overcoming a variety of diseases.
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Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation
Peter Baluk,Tuomas Tammela,Erin Ator,Natalya Lyubynska,Marc G. Achen,Daniel J. Hicklin,Michael Jeltsch,Tatiana V. Petrova,Bronislaw Pytowski,Steven A. Stacker,Seppo Ylä-Herttuala,David A. Jackson,Kari Alitalo,Donald M. McDonald +13 more
TL;DR: It is suggested that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction, and Correction of defective lymphang iogenesis may benefit the treatment of asthma and other inflammatory airway diseases.
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VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification:
J. Dai,A B M Rabie +1 more
TL;DR: Current findings on endochondral ossification are discussed, with emphasis on VEGF-A action in osteoblasts,chondroblasts, and chondroclasts/osteoclasts and regulatory mechanisms involving oxygen tension, and some growth factors and hormones.
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Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia.
Kurt R. Stenmark,Steven H. Abman +1 more
TL;DR: It is speculated that understanding basic mechanisms that regulate and determine vascular growth will lead to new clinical strategies to improve the long-term outcome of premature babies with BPD.
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Spatial and temporal dynamics of the endothelium.
TL;DR: The goals of this review are to consider mechanisms of endothelial cell heterogeneity, discuss the bench‐to‐bedside gap in endothelial biomedicine, revisit definitions for endothelium activation and dysfunction, and propose new goals in diagnosis and therapy.
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